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Childhood Soft Tissue Sarcoma Treatment

General Information

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, pediatric radiation oncologist, pediatric hematologist/oncologist, rehabilitation specialist, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

Incidence

Pediatric soft tissue sarcomas (STSs) are a heterogenous group of malignant tumors that originate from primitive mesenchymal tissue and account for 7% of all childhood tumors.[3] Multidisciplinary evaluation in centers that have surgical and radiotherapeutic expertise is of critical importance to ensure the best clinical outcome for these patients. Although surgery with or without radiation therapy can be curative for a significant proportion of patients, the addition of chemotherapy might benefit subsets of children with the disease; therefore, enrollment into clinical trials is encouraged.

Rhabdomyosarcoma, a tumor of striated muscle, is the most common STS in children aged 0 to 14 years and accounts for 50% of tumors in this age group.[4] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.) The remaining STSs are commonly referred to as nonrhabdomyosarcomatous STSs and account for about 3% of all childhood tumors.[5] This heterogeneous group of tumors includes neoplasms of:[6]

In children, synovial sarcoma, fibrosarcoma, fibrohistiocytic tumors, and malignant peripheral nerve sheath tumors predominate.[7,8] The distribution of STSs by histology and age, based on the Surveillance Epidemiology and End Results (SEER) information from 1975 to 2008, is depicted in Table 1. The distribution of histologic types by age is shown in Figure 1.

Table 1. Age Distribution of Soft Tissue Sarcomas (STSs) in Children Aged 0 to 19 Years (SEER 1975–2008)

Figure 1. The distribution of nonrhabdomyosarcomatous soft tissue sarcomas in children aged 0 to 19 years, as reported by the Surveillance Epidemiology and End Results program from 1975 to 2008.

Nonrhabdomyosarcomatous STSs are more common in adolescents and adults,[6] and most of the information regarding treatment and natural history of the disease in younger patients has been based on adult studies.

Risk Factors

Some genetic and environmental factors have been associated with the development of nonrhabdomyosarcomatous STS:

Werner syndrome: Werner syndrome is characterized by spontaneous chromosomal instability, resulting in increased susceptibility to cancer and premature aging. An excess of STSs has been reported in patients with Werner syndrome.[14]

Retinoblastoma gene: Germline mutations of the retinoblastoma gene have been associated with an increased risk of developing STSs, particularly leiomyosarcoma.[15]

Epstein-Barr virus infection in patients with AIDS: Some nonrhabdomyosarcomatous STSs (e.g., leiomyosarcoma) have been linked to Epstein-Barr virus infection in patients with AIDS.[5,17]

Clinical Presentation

Although nonrhabdomyosarcomatous STSs can develop in any part of the body, they arise most commonly in the trunk and extremities.[7,18,19] These neoplasms can present initially as an asymptomatic solid mass, or they may be symptomatic because of local invasion of adjacent anatomical structures.

Systemic symptoms (e.g., fever, weight loss, and night sweats) are rare. Hypoglycemia and hypophosphatemic rickets have been reported in cases of hemangiopericytoma, whereas hyperglycemia has been noted in patients with fibrosarcoma of the lung.[20]

Diagnosis

When a suspicious lesion is identified, it is crucial that a complete workup, followed by adequate biopsy be performed. Generally, it is better to image the lesion before any interventions. Plain films can be used to rule out bone involvement and detect calcifications that may be seen in soft tissue tumors such as extraskeletal osteosarcoma or synovial sarcoma. Chest radiography and computed tomography (CT) of chest are essential to assess the presence of metastases. CT can be used to image intra-abdominal tumors, such as liposarcoma, and magnetic resonance imaging (MRI) can be used for extremity lesions.

Nonrhabdomyosarcomatous soft tissue tumors are fairly readily distinguished pathologically from rhabdomyosarcoma and Ewing sarcoma; however, classification of childhood nonrhabdomyosarcomatous STS type is often difficult. A core-needle biopsy or small incisional biopsy that obtains adequate tumor tissue is crucial to allow for conventional histology, immunocytochemical analysis, and other studies such as light and electron microscopy, cytogenetics, fluorescence in situ hybridization, and molecular pathology,[21,22] given the diagnostic importance of translocations. Needle biopsy techniques must obtain an adequate tissue sample and usually require obtaining multiple cores of tissue. Image guidance using ultrasound, CT scan, or MRI may be necessary to ensure a representative biopsy.[23] Incisional biopsies are acceptable but should not compromise subsequent wide local excision, and excisional biopsy of the lesion must be avoided. Transverse extremity incisions should be avoided to reduce skin loss, as should extensive surgical procedures before definitive diagnosis. For these reasons, open biopsy or multiple core-needle biopsies are strongly encouraged so that adequate tumor tissue can be obtained to allow for crucial studies to be performed and to avoid limiting future treatment options.

A single-institution analysis of adolescents and adults compared patients with unplanned excision of STS to stage-matched controls. In this retrospective analysis, unplanned initial excision of STS resulted in increased risk for local recurrence, metastasis, and death, and this increase was greatest for high-grade tumors.[24][Level of evidence: 3iiA]

Many nonrhabdomyosarcomatous STSs are characterized by chromosomal abnormalities. Some of these chromosomal translocations lead to a fusion of two disparate genes. The resulting fusion transcript can be readily detected by using polymerase chain reaction-based techniques, thus facilitating the diagnosis of those neoplasms that have translocations. Some of the most frequent aberrations seen in nonrhabdomyosarcomatous soft tissue tumors are listed in Table 2.

The prognosis of nonrhabdomyosarcomatous STS tumors varies greatly depending on the histologic grade, invasiveness, tumor size, resectability, use of radiation therapy, site of primary tumor, and presence of metastases.[36,37,38] Some pediatric nonrhabdomyosarcomatous STSs are associated with a better outcome. For instance, infantile fibrosarcoma, presenting in infants and children younger than 4 years, has an excellent prognosis given that the tumor is highly chemosensitive and surgery alone can cure a significant number of these patients.[5]

Soft tissue sarcomas in older children and adolescents often behave similarly to those in adult patients.[5,21]

In a pooled analysis from U.S. and European pediatric centers, outcome was better for patients who received radiation therapy than for patients who did not, and outcome was better for patients whose tumor-removal procedure was deemed complete than for patients whose tumor removal was incomplete.[40][Level of evidence: 3iiiA]

Because long-term related morbidity must be minimized while disease-free survival is maximized, the ideal therapy for each patient must be carefully and individually determined utilizing these prognostic factors before initiating therapy for these patients.[18,42,43,44,45,46]

Related Disease Summaries

Refer to the following PDQ summaries for information about other types of sarcoma:

Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.

Histopathological Classification

The WHO lists the following cell types in its classification of STSs:[1,2]

This summary focuses on high-grade sarcomas and low-grade tumors that present special problems in the pediatric and adolescent population, including desmoid tumor and infantile fibrosarcoma. For many low-grade STSs, surgical resection is curative and there is no need for additional therapy.

a Not a high-grade tumor; b The category of fibrosarcoma can be inclusive of fibrosarcomatous differentiation in dermatofibrosarcoma protuberans; c Cutaneous angiosarcoma may be difficult to stage using the American Joint Committee on Cancer system.

Staging and Grading Systems for Childhood Soft Tissue Sarcoma

Clinical staging has an important role in predicting the clinical outcome and determining the most effective therapy for pediatric soft tissue sarcomas (STSs). As yet, there is no well-accepted staging system that is applicable to all childhood sarcomas. The system from the American Joint Committee on Cancer (AJCC) that is used for adults has not been validated in pediatric studies.

Although a standardized staging system for pediatric nonrhabdomyosarcomatous STS does not exist, the last Children's Oncology Group (COG) trial used the sixth edition AJCC cancer staging manual for STSs (with central pathology review) (see Tables 3–6 below).[1]

Two systems are currently in use for staging pediatric nonrhabdomyosarcomatous STS tumors.

Surgico-pathologic staging system: The surgico-pathologic staging system used by the Intergroup Rhabdomyosarcoma Study (see below) is based on the amount, or extent, of tumor that remains after initial surgery and whether the disease has metastasized.[2]

TNM staging system: The other system typically used to stage pediatric soft tissue tumors is the TNM system of the International Union Against Cancer. Staging is based on the extent of the tumor (T), the extent of spread to the lymph nodes (N), and the presence of metastasis (M).[3]

IIB: Regional disease with involved nodes completely resected with no microscopic disease. The most proximal (to the patient, most distal to the tumor) regional lymph node must be negative.

IIC: Regional disease with involved nodes grossly resected but with evidence of residual microscopic disease at the primary site and/or histologic involvement of the most proximal regional lymph node in the dissection.

Group IV: Any localized or regional tumor with distant metastases present at the time of diagnosis. This includes the presence of malignant cells in effusions (pleural, peritoneal) and/or cerebrospinal fluid (rare).

Recurrent/progressive disease

Any STS that recurs after initial treatment or progresses after radiation therapy, chemotherapy, or initial surgery.

TNM Staging System

The AJCC has designated staging by the four criteria of tumor size, nodal status, histologic grade, and metastasis.[4]

Table 3. Primary Tumor (T)a

b Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia.

In most cases, accurate histopathologic classification of STSs alone does not yield optimal information about their clinical behavior. Therefore, several histologic parameters, including degree of cellularity, cellular pleomorphism, mitotic activity, degree of necrosis, and invasive growth, are evaluated in the grading process. This process is used to improve the correlation between histologic findings and clinical outcome.[5] In children, grading of STSs is compromised by the good prognosis of certain tumors, such as infantile fibrosarcoma and hemangiopericytoma, which have a good prognosis in children younger than 4 years, and also angiomatoid fibrous histiocytoma and dermatofibrosarcoma protuberans, which may recur locally if incompletely excised, but usually do not metastasize.

Testing a grading system within the pediatric population is difficult because of the rarity of these neoplasms. In March 1986, the Pediatric Oncology Group (POG) conducted a prospective study on pediatric STSs other than rhabdomyosarcoma and devised the grading system that is shown below. Analysis of outcome for patients with localized STSs other than rhabdomyosarcoma demonstrated that patients with grade 3 tumors fared significantly worse than those with grade 1 or grade 2 lesions. This finding suggests that this system can accurately predict the clinical behavior of nonrhabdomyosarcomatous STS.[5,6,7]

The grading systems developed by the POG and the French Federation of Comprehensive Cancer Centers (Fédération Nationale des Centres de Lutte Contre Le Cancer [FNCLCC]) Sarcoma Group are described below. These grading systems are being compared by the central review pathologists on the COG-ARST0332 study. The study has closed and results are pending.

Grade III lesions are similar to Grade II lesions and include certain tumors known to be clinically aggressive by virtue of histologic diagnosis and non-Grade I tumors (with >4 mitoses per 10 high-power fields or >15% necrosis):

Pleomorphic or round-cell liposarcoma.

Mesenchymal chondrosarcoma.

Extraskeletal osteogenic sarcoma.

Malignant triton tumor.

Alveolar soft part sarcoma.

Any other sarcoma not in grade I with >15% necrosis and/or ≥5 mitotic figures per 10 high-power fields (40X objective).

Any other sarcoma not included in grade I in which more than 15% of the surface area is necrotic or in which there are more than four mitotic figures per ten high-power fields (40X objective) is considered a grade III lesion. Marked atypia and cellularity are less predictive but may assist in placing tumors in this category.

FNCLCC grading system

The FNCLCC histologic grading system was developed for adults with STS. The purpose of the grading system is to predict which patients will develop metastasis and subsequently benefit from adjuvant chemotherapy.[8,9] The system is described in Tables 7 and 8.

Table 8. Histologic Grade Determined by Total Score

Total Score

Histologic Grade

2–3

Grade I

4–5

Grade II

6–8

Grade III

Prognostic Significance of Tumor Grading

The two grading systems described above have proven to be of prognostic value in pediatric and adult nonrhabdomyosarcomatous STSs.[10,11,12,13,14] In a study of 130 tumors from children and adolescents with nonrhabdomyosarcomatous STS enrolled in three prospective clinical trials, a correlation was found between the POG-assigned grade and the FNCLCC-assigned grade. However, grading did not correlate in all cases; 44 tumors received discrepant grades and their clinical outcome was intermediate between those who were assigned grades 1 and 2 or 3 in both systems. A mitotic index of 10 or greater emerged as an important prognostic factor.[15] The recently completed COG-ARST0332 trial will analyze data comparing the POG and FNCLCC pathologic grading systems to determine which system better correlates with clinical outcomes.

In a review of a large adult series of nonrhabdomyosarcomatous STSs, superficial extremity sarcomas had a better prognosis than deep tumors. Thus, in addition to grade and size, the depth of invasion of the tumor should be considered.[16]

Several adult and pediatric series have shown that patients with large or invasive tumors have a significantly worse prognosis than do those with small, noninvasive tumors. A retrospective review of STSs in children and adolescents suggests that the 5 cm cutoff used for adults with STS may not be ideal for smaller children, especially infants. The review identified an interaction between tumor diameter and body surface area.[17] This relationship requires further study to determine the therapeutic implications of the observation.

Treatment Option Overview

Because of the rarity of pediatric nonrhabdomyosarcomatous soft tissue sarcomas (STSs), all children, adolescents, and young adults with these tumors should have their treatment coordinated by a multidisciplinary team comprising pediatric oncologists, pathologists, surgeons, and radiation oncologists. To better define the tumors' natural history and response to therapy, children with rare neoplasms should be considered for entry into national or institutional treatment protocols. Information about ongoing clinical trials is available from the NCI Web site.

Surgery

Every attempt should be made to resect the primary tumor with negative margins before or after chemotherapy. Involvement of a surgeon with special expertise in the resection of STSs in the decision is highly desirable.

The timing of surgery depends on an assessment of the feasibility and morbidity of surgery. If the initial operation fails to achieve pathologically negative tissue margins or if the initial surgery was done without the knowledge that cancer was present, a re-excision of the affected area should be performed to obtain clear, but not necessarily wide, margins.[1,2,3,4,5] This surgical tenet is true even if no mass is detected by magnetic resonance imaging after initial surgery.[6]; [7][Level of evidence: 3iiA]

Regional lymph node metastases at diagnosis are unusual and appear most likely with epithelioid and clear cell sarcomas.[8] Sentinel lymph node mapping is employed at some centers to identify the regional nodes that are the most likely to be involved, although its widespread contribution to the staging and management of these tumors has yet to be clearly defined.[9,10,11]

Radiation Therapy

Considerations for radiation therapy are based on the potential for surgery, with or without chemotherapy, to obtain local control without loss of critical organs, or significant functional, cosmetic or psychological impairment. This will vary according to patient variables, including age and gender, and tumor variables, including histopathology, site, size, and grade. Radiation therapy considerations include the same patient and tumor variables, surgical margin status, and expectations for radiation-induced morbidities such as impaired bone or muscle development, organ damage, or second malignancy. Radiation therapy can be given preoperatively or postoperatively, and the radiation field size and dose will again be based on patient and tumor variables and the operability of the tumor.

In general, radiation is indicated for patients with inadequate surgical margins and for larger, high-grade tumors.[12,13] This is particularly important in high-grade tumors with tumor margins smaller than 1 cm.[14,15]; [16][Level of evidence: 3iiDiv] With combined surgery and radiation therapy, local control of the primary tumor can be achieved in more than 80% of patients.[17,18] Preoperative radiation therapy has been associated with excellent local control rates.[19,20,21] This approach has the advantage of treating smaller tissue volumes because it does not necessitate treating a postsurgical bed; it also has the advantage of somewhat lower radiation doses because relative hypoxia from surgical disruption of vasculature and scarring is not present. Preoperative radiation therapy has been associated with an increased rate of wound complications in adults, primarily in lower extremity tumors, but the degree of this is questionable.[22] Conversely, preoperative radiation therapy may lead to less fibrosis than with postoperative approaches, perhaps due to the smaller treatment volume and dose.[23] Brachytherapy and intraoperative radiation may be applicable in select situations.[18,24,25]; [26][Level of evidence: 3iiiDii] In the recently closed COG-ARST0332 trial, preoperative radiation therapy was recommended for patients who presented with unresected tumor. The use of postoperative radiation therapy for patients who presented after primary resection was dependent on the tumor size, grade, and margin status.

Retroperitoneal sarcomas are a special issue since radiosensitivity of the bowel to injury makes postoperative radiation therapy less desirable. Reasons for this include the postoperative adhesions and bowel immobility that increase the risk of damage from any given radiation dose. This is in contrast to the preoperative approach in which the tumor often displaces bowel outside of the radiation field, and any exposed bowel is more mobile, which decreases exposure to specific bowel segments.

Radiation volume and dose depend on all patient, tumor, and surgical variables as noted above. Considerations include patient age and growth potential, the ability to avoid critical organs, epiphyseal plates, and lymphatics (but not the neurovascular bundles that are relatively radiation tolerant), and the functional/cosmetic outcome. Radiation margins are typically 2 cm to 4 cm longitudinally, and encompassing fascial planes axially. Radiation doses are typically 45 Gy to 50 Gy preoperatively, with consideration for postoperative boost of 10 Gy to 20 Gy if resection margins are microscopically or grossly positive, or planned brachytherapy if the resection is predicted to be subtotal. However, data documenting the efficacy of a postoperative boost are lacking.[27] The postoperative radiation dose is 55 Gy to 60 Gy, or rarely, higher in the situation where unresectable gross residual disease exists.

Chemotherapy

The role of adjuvant (postoperative) chemotherapy remains controversial.[28] A meta-analysis of updated data from adult STS patients from all available randomized trials concluded that recurrence-free survival was better with adjuvant chemotherapy for patients with high-grade tumors larger than 5 cm.[29] The largest prospective pediatric trial failed to demonstrate any benefit with adjuvant vincristine, dactinomycin, cyclophosphamide, and doxorubicin.[17] In a European trial, adults with completely resected STS were randomly assigned to observation or adjuvant chemotherapy with ifosfamide and doxorubicin. Adjuvant chemotherapy was not associated with improved event-free survival or overall survival. It is difficult to extrapolate this trial to pediatric patients because the trial included (1) a wide variety of histologies; (2) a relatively low dose of ifosfamide; (3) patients assigned to chemotherapy had definitive radiation delayed until completion of chemotherapy; and (4) almost one-half of the patients in the trial had intermediate-grade tumors. In the discussion section, the authors merged their patients with previously published series, including those from the European meta-analysis, and concluded that the results suggested a benefit for adjuvant chemotherapy.[30][Level of evidence: 1iiA]

Special Treatment Considerations for Children With STS

Many therapeutic strategies for children and adolescents with soft tissue tumors are similar to those for adult patients, although there are important differences. For example, the biology of the neoplasm in pediatric patients may differ dramatically from that of the adult lesion. Additionally, limb-sparing procedures are more difficult to perform in pediatric patients. The morbidity associated with radiation therapy, particularly in infants and young children, may be much greater than that observed in adults.[31]

Improved outcomes with multimodality therapy in adults and children with STSs over the past 20 years has caused increasing concern about the potential long-term side effects of this therapy in children, especially when considering the expected longer life span of children versus adults. Therefore, to maximize tumor control and minimize long-term morbidity, treatment must be individualized for children and adolescents with nonrhabdomyosarcomatous STS. These patients should be enrolled in prospective studies that accurately assess any potential complications.[32]

Treatment of Newly Diagnosed Childhood Soft Tissue Sarcoma

Adipocytic Tumors

Liposarcoma

Liposarcoma is rare in the pediatric population. In a review of 182 pediatric patients with adult-type sarcomas, only 14 had a diagnosis of liposarcoma.[1] One retrospective study identified 34 patients younger than 22 years from 1960 to 2011.[2] There were roughly equal numbers of male and female patients and the median age was 18 years. In an international clinicopathological review, the characteristics of 82 cases of pediatric liposarcoma were reported. The median age was 15.5 years and females were more commonly affected.[3] In both reports, the great majority of patients had myxoid liposarcoma.

Liposarcomas can be roughly divided into the following four large groups:

Atypical lipomatous neoplasm/well-differentiated liposarcoma. These tumors do not metastasize unless they undergo dedifferentiation.

Myxoid liposarcoma. Pure myxoid liposarcomas are characterized by a t(12;16)(q13;p11) translocation and can metastasize but usually have an excellent outcome in the absence of a round cell component.

Dedifferentiated liposarcoma.

Pleomorphic liposarcoma.

The great majority of liposarcomas in the pediatric and adolescent age range are low grade. Myxoid liposarcoma is typically low grade. Pleomorphic liposarcoma is typically high grade and much more likely to develop metastasis. Metastasis to lymph nodes is very uncommon, and the great majority of metastases are pulmonary. Tumors arising in the periphery are more likely to be low grade and myxoid. Tumors arising centrally are more likely to be high grade, pleomorphic, and present with metastasis or recur with metastasis.

Treatment

Surgery is the most important treatment for liposarcoma. After surgical resection of myxoid liposarcoma, event-free survival (EFS) and overall survival (OS) are roughly 90%. Local recurrences have been seen and are controlled with a second resection of the tumor. Higher grade or central tumors are associated with a significantly higher risk of death. In a retrospective review, 5-year survival for central tumors was 42%. In the international review, seven of ten patients with pleomorphic myxoid liposarcoma died because of their disease.[3] If initial surgery is incomplete, re-excision should be performed to achieve a wide margin of resection. There are reports of the use of chemotherapy to decrease the size of liposarcoma before surgery to facilitate complete resection, particularly in central tumors.[4,5] The role of adjuvant chemotherapy for liposarcoma is poorly defined. There does not appear to be a need for any adjuvant therapy for completely resected myxoid liposarcoma. Even with the use of adjuvant chemotherapy, the survival of pleomorphic liposarcoma remains poor.[6]

Chondro-osseous Tumors

Chondro-osseous tumors include the following tumor subtypes:

Extraskeletal chondrosarcoma (mesenchymal and other variants).

Extraskeletal osteosarcoma.

Extraskeletal chondrosarcoma (mesenchymal and other variants)

Mesenchymal chondrosarcoma is a highly malignant tumor with a propensity to spread to the lungs.

Treatment

A review of 15 patients younger than 26 years from the German Cooperative Soft Tissue Sarcoma Study Group (11 with soft-tissue lesions) and the German-Austrian-Swiss Cooperative Osteosarcoma Study Group (four with primary bone lesions) protocols suggests that complete surgical removal, or incomplete resection followed by radiation therapy, is necessary for local control.[7][Level of evidence: 3iiA]

Multiagent chemotherapy may decrease the likelihood of lung metastases: OS at 10 years was 67%, compared with approximately 20% in an earlier series of young patients.[8]

Extraskeletal osteosarcoma

Extraskeletal osteosarcoma is extremely rare in the pediatric and adolescent age range. A 2003 review identified only ten case reports in the medical literature.[9]

Extraskeletal osteosarcoma is associated with a high risk of local recurrence and pulmonary metastasis.[10]

Treatment

The primary therapy for extraskeletal osteosarcoma is surgical resection of the primary tumor. Chemotherapy for extraskeletal osteosarcoma has not been well studied. It has been recommended that the treatment for extraskeletal osteosarcoma abide by the soft tissue sarcoma (STS) guidelines, rather than the guidelines for osteosarcoma of bone.[9] A report of a series of adult patients with extraskeletal osteosarcoma suggested that adjuvant chemotherapy reduced the risk of recurrence.[10] Extraskeletal osteosarcoma may be more chemosensitive in young patients than in adults.[9] A retrospective analysis of the German Cooperative Osteosarcoma Study identified a favorable outcome for extraskeletal osteosarcoma treated with surgery and conventional osteosarcoma chemotherapy.[11] (Refer to the PDQ summary on Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment for more information.)

Fibroblastic/Myofibroblastic Tumors

Fibroblastic/myofibroblastic tumors include the following tumor subtypes:

Desmoid tumor.a

Fibrosarcoma.

Infant fibrosarcoma.

Adult-type fibrosarcoma.

Inflammatory myofibroblastic tumor.a

Low-grade fibromyxoid sarcoma.

Sclerosing epithelioid fibrosarcoma.

a Not a high-grade tumor.

Desmoid tumors

Desmoid tumors are also known as aggressive fibromatoses.

Desmoid tumors are low-grade malignancies with extremely low potential to metastasize. The tumors are locally infiltrating, and surgical control can be difficult because of the need to preserve normal structures. These tumors also have a high potential for local recurrence. Desmoid tumors have a highly variable natural history, including well documented examples of spontaneous regression.[12] Mutations in exon 3 of the beta-catenin gene are seen in over 80% of desmoid tumors and the mutation 45F has been associated with an increased risk of disease recurrence.[13] Repeated surgical resection can sometimes bring recurrent lesions under control.[14]

A small number of desmoid tumors may occur in association with a mutation in the adenomatous polyposis coli (APC) gene (associated with intestinal polyps and a high incidence of colon cancer). In a study of 519 patients older than 10 years with a diagnosis of desmoid-type fibromatosis, 39 (7.5%) were found to have familial adenomatous polyposis (FAP) (a possible underestimation).[15] The patients with FAP and desmoid tumors were younger, more often male, and had more abdominal wall or mesenteric tumors than did patients with desmoid tumors without FAP. A family history of colon cancer or the presence of congenital hyperplasia of the retinal pigment epithelium [16,17] or location of the desmoid tumor in the abdomen or abdominal wall [15] should prompt referral to a genetic counselor. Currently, there are no general recommendations for genetic testing in children with desmoid tumors. Pathology and molecular characteristics of the tumor only provide guidance for screening. If the tumor has a somatic CTNNB1 mutation, screening is not necessary, because the APC gene mutation has not been described in this setting. If a CTNNB1 mutation is not identified, screening for the APC mutation may be warranted.[18,19]

Treatment

The treatment of choice is resection to achieve clear margins. If postoperative margins are positive, 70% of patients will have a recurrence of disease. Postoperative radiation therapy is a consideration when progression would entail additional surgery that might cause functional or cosmetic compromise and if radiation is considered acceptable in terms of morbidities. When the diagnosis is known and complete surgical excision is not feasible, and if the tumor poses significant potential for mortality or morbidity, preoperative strategies may include the following:[20,21]

Chemotherapy.

Antiestrogen therapy.

Nonsteroidal anti-inflammatory agent therapy.

External-beam radiation therapy.

Evaluation of the benefit of interventions for treatment of desmoid tumors has been extremely difficult, because desmoid tumors have a highly variable natural history.

Large adult series and smaller pediatric series have reported long periods of disease stabilization and even regression without systemic therapy.[14,22]; [23][Level of evidence: 3iiiDi] Combination chemotherapy using vinblastine and methotrexate produced objective responses in about one-third of patients with recurrent or unresectable desmoid tumors.[20] A small series of mainly adult patients (N = 19) with desmoid tumors were treated with imatinib mesylate and showed infrequent objective responses.[24] A series of mainly adult patients with familial adenomatous polyposis and unresectable desmoid tumors that were unresponsive to hormone therapy showed that doxorubicin plus dacarbazine followed by meloxicam (a nonsteroidal anti-inflammatory agent) can be safely administered and can induce responses.[25] Pegylated liposomal doxorubicin has also been used with some responses.[26] Hydroxyurea may be useful, but more data are needed.[27]

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac have been used in single cases for desmoid tumors; the responses seen were usually disease stabilization. Similar results have been seen with antiestrogen treatment, usually tamoxifen.[28] A prospective trial of the combination of tamoxifen and sulindac reported few side effects, although asymptomatic ovarian cysts were common in girls. This combination showed relatively little activity, as measured by rates of response and progression-free survival.[29][Level of evidence: 2Diii]

Radiation has been used for unresectable desmoid tumors or adjuvantly for tumors with inadequate resections. The potential long-term complications of radiation therapy, especially subsequent neoplasms, make using this modality less appealing in a young population.[30]

Partially excised or recurrent lesions that do not pose a significant danger to vital organs may be monitored closely if other treatment alternatives are not available.[14,31,32,33,34] Whenever possible, however, the treatment of choice is complete resection.

Fibrosarcoma

There are two distinct types of fibrosarcoma in children and adolescents: infantile fibrosarcoma (also called congenital fibrosarcoma) and fibrosarcoma that is indistinguishable from fibrosarcoma seen in adults. These are two distinct pathologic diagnoses.

Infantile fibrosarcoma

Infantile fibrosarcoma usually occurs in children younger than 1 year. It occasionally occurs in children up to age 4 years. It usually presents with a rapidly growing mass, often noted at birth or even seen in prenatal ultrasound. The tumors are often quite large at the time of presentation. The tumor usually has a characteristic cytogenetic translocation t(12;15)(ETV-NTRK3). Infantile fibrosarcoma shares this translocation and a virtually identical histologic appearance with mesoblastic nephroma. These tumors have a low incidence of metastases at diagnosis.

Treatment

Complete resection is curative in the majority of patients with infantile fibrosarcoma. However the large size of the lesion frequently makes resection without major functional consequences impossible (for instance, tumors of the extremities often require amputation for complete excision). Preoperative chemotherapy has made a more conservative surgical approach possible; agents active in this setting include vincristine, dactinomycin, cyclophosphamide, and ifosfamide.[35,36,37]; [38][Level of evidence: 3iiA]; [39][Level of evidence: 3iiB]

Adult-type fibrosarcoma

These tumors lack the translocation seen in infantile fibrosarcomas. They present like the great majority of nonrhabdomyosarcomas and the management approach is similar.

Dermatofibrosarcoma protuberans

Dermatofibrosarcoma is a rare tumor, but many of the reported cases arise in children.[40] The tumor has a consistent chromosomal translocation t(17;22)(q22;q13) that juxtaposes the COL1A1 gene with the PDGF-beta gene.

Treatment

Most dermatofibrosarcoma tumors can be cured by complete surgical resection. Wide excision with negative margins or Mohs or modified Mohs surgery will prevent most tumors from recurring.[41]

In retrospective reviews, adjuvant radiation therapy after incomplete excision may have decreased the likelihood of recurrence.[42,43]

When surgical resection cannot be accomplished or the tumor is recurrent, treatment with imatinib has been effective.[44,45,46]

Guidelines for workup and management of dermatofibrosarcoma protuberans have been published.[47]

Complete surgical removal, when feasible, is the mainstay of therapy.[52] There are no well-documented responses to chemotherapy. A case report described a partial response in a patient with recurrent inflammatory myofibroblastic tumor who was treated with crizotinib, an ATP-competitive inhibitor of the ALK and MET tyrosine kinases.[53] There are case reports of response to either steroids or NSAIDs.[54,55]

Low-grade fibromyxoid sarcoma

Low-grade fibromyxoid sarcoma is somewhat misnamed, because its appearance is deceptively benign, but its behavior is malignant, although rather indolent.[56] In a review, 21 of 33 patients had local recurrences after intervals of up to 15 years (median, 3.5 years) and 15 had metastases, mostly in the lungs and pleura, after periods of up to 45 years (median, 5 years), indicating that follow-up must be lifelong.[56] Even after metastases occur, the course may be indolent.[57]

The limited treatment information for low-grade fibromyxoid sarcoma is summarized in the review above. This tumor is not very chemosensitive and there are little data regarding the use of chemotherapy and/or radiation therapy.

Myxofibrosarcoma, low grade

Myxofibrosarcoma, low grade, is a rare lesion, especially in childhood. It is typically treated with complete surgical resection.

Sclerosing epithelioid fibrosarcoma

Sclerosing epithelioid fibrosarcoma is another rare, usually low-grade, sarcoma. It is typically treated with complete surgical excision.

Skeletal Muscle Tumors

Rhabdomyosarcoma

There are three forms of rhabdomyosarcoma:

Embryonal, plus subtypes of botryoid and spindle cells.

Alveolar.

Pleomorphic, also known as anaplastic sarcoma.

Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.

Smooth Muscle Tumors

Leiomyosarcoma

A 24-year retrospective analysis of the Italian cooperative group identified one child with leiomyosarcoma.[5] A retrospective analysis of the St. Jude Children's Research Hospital (SJCRH) experience from 1962 to 1996 identified 40 children with nonrhabdomyosarcomatous STS; none had leiomyosarcoma.[58] Among 43 children with HIV/AIDS who developed tumors, eight developed Epstein-Barr virus–associated leiomyosarcoma.[59] Survivors of hereditary retinoblastoma have a statistically significant increased risk of developing leiomyosarcoma and 78% of these were diagnosed 30 or more years after the initial diagnosis of retinoblastoma.[60]

So-called Fibrohistiocytic Tumors

So-called fibrohistiocytic tumors include the following tumor subtypes:

Plexiform fibrohistiocytic tumor.

Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma.

Giant cell.

Inflammatory.

Myxoid/high-grade myxofibrosarcoma.

Pleomorphic.

Plexiform fibrohistiocytic tumor

Plexiform histiocytic tumor is a rare, low- to intermediate-grade tumor that most commonly affects children and young adults. Depending on the series, the median age at presentation ranges from 8 to 14.5 years; however, the tumor has been described in patients as young as 3 months.[61,62]

The tumor commonly arises as a painless mass in the skin or subcutaneous tissue and most often involves the upper extremities, including the fingers, hand, and wrist.[63,64,65] There are rare reports of spread to regional lymph nodes or the lungs.[61,65,66]

No consistent chromosomal anomalies have been detected but a t(4;15)(q21;q15) has been reported.[67]

Treatment

Surgery is the treatment of choice but local recurrence has been reported in 12% to 50% of cases.[68]

At one time, malignant fibrous histiocytoma was the single most common histiotype among adults with STSs. Since it was first recognized in the early 1960s, malignant fibrous histiocytoma has been plagued by controversy in terms of both its histogenesis and its validity as a clinicopathologic entity. The latest World Health Organization classification no longer includes malignant fibrous histiocytoma as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma.[69]

This entity accounts for 2% to 6% of all childhood STSs.[70] These tumors can arise in previously irradiated sites or as a second malignancy in patients with retinoblastoma.

These tumors occur mainly in the second decade of life. In a series of ten patients, the median age was 10 years and the tumor was most commonly located in the extremities. In this series, all tumors were localized and five of nine (for whom follow-up was available) were alive in first remission.[70] In another series of 17 pediatric patients with malignant fibrous histiocytoma, the median age at diagnosis was 5 years and the extremities were involved in eight cases.[71] All patients with metastatic disease died and two patients experienced a clinical response to a doxorubicin-based regimen.

Smaller tumor size—In a multivariate analysis, only tumor size and nuclear p53 expression were found to be independent predictors of disease-specific survival.[74]

Localized disease; no metastasis at presentation—A retrospective review of 140 patients with malignant peripheral nerve sheath tumor from the MD Anderson Cancer Center included children and adolescents. The disease-specific survival at 10 years was 32%. In this series, presence of metastatic disease was associated with a much worse prognosis. For patients with localized disease, there was no significant difference in outcome between patients with and without NF1.[74]

Lower stage.

Lower histologic grade.

Extremity as the primary site.

It is not clear whether the absence of NF1 is a favorable prognostic factor as it has been associated with both favorable [73] and unfavorable outcomes.[72,73,75]

Treatment

There is agreement that complete surgical removal of the tumor, whenever possible, is the mainstay of treatment. The role of radiation therapy is difficult to assess, but durable local control of known postsurgical microscopic residual tumor is not assured after radiation therapy. Chemotherapy has achieved objective responses in childhood malignant peripheral nerve sheath tumor. A large retrospective analysis of the German and Italian experience with malignant peripheral nerve sheath tumor reported that 65% of measurable tumors had objective responses to ifosfamide-containing chemotherapy regimens, but the analysis did not conclusively demonstrate improved survival for chemotherapy.[72] This retrospective analysis also noted a trend toward improved outcome with adjuvant radiation therapy.[72] A series of 37 young patients with malignant peripheral nerve sheath tumor and NF1 showed that most patients had large invasive tumors that were poorly responsive to chemotherapy; progression-free survival was 19% and 5-year OS was 28%.[76] The role of adjuvant chemotherapy after resection of malignant peripheral nerve sheath tumor has not been prospectively evaluated.

Tumors of Uncertain Differentiation

Tumors of uncertain differentiation include the following tumor subtypes:

Alveolar soft part sarcoma.

Clear cell sarcoma of soft tissue.

Desmoplastic small round cell tumor.

Epithelioid sarcoma.

Extrarenal rhabdoid tumor.

Extraskeletal myxoid chondrosarcoma.

Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor.

Synovial sarcoma.

Undifferentiated sarcoma; sarcoma, not otherwise specified (NOS).

Alveolar soft part sarcoma

This is a tumor of uncertain histogenesis. A consistent chromosomal translocation t(X;17)(p11.2;q25) juxtaposes the ASPSCR1 gene with the TFE3 gene.[77,78] In children, alveolar soft part sarcoma often presents with metastases [79] and sometimes has a very indolent course. A subset of renal tumors found in young people was previously considered to be renal cell carcinoma, but the subset now appears to be genetically related to alveolar soft part sarcoma.[80]

Pediatric alveolar soft part sarcoma seems to have a better outcome than its adult counterpart.[81] In a series of 19 treated patients, one group reported a 5-year OS rate of 80%, a 91% OS rate for patients with localized disease, a 100% OS rate for patients with tumors 5 cm or smaller, and a 31% OS rate for patients with tumors larger than 5 cm.[82] In another series of 33 patients, OS was 68% at 5 years from diagnosis and 53% at 10 years from diagnosis. Survival was better for smaller tumors (≤5 cm) and completely resected tumors.[83][Level of evidence: 3iiA]

Treatment

The standard approach is complete resection of the primary lesion.[82] If complete excision is not feasible, radiation therapy should be administered.

The value of adjuvant chemotherapy in completely resected alveolar soft part sarcoma remains unproven, particularly because patients with unresected or metastatic tumors failed to respond to chemotherapeutic agents frequently used to treat STSs.[84] Alveolar soft part sarcoma is considered a chemoresistant tumor.[85] There are sporadic reports of objective responses to interferon-alpha, bevacizumab, and sunitinib.[86,87,88,89]

Patients with alveolar soft part sarcoma may relapse several years after a prolonged period of apparent remission.[90] Because these tumors are rare, all children with alveolar soft part sarcoma should be considered for prospective clinical trials.

Treatment options under clinical evaluation for alveolar soft part sarcoma

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

NCT00942877 (Phase II Study of Cediranib in Patients With Alveolar Soft Part Sarcoma): This phase II study of cediranib in patients with alveolar soft part sarcoma is being conducted at the Clinical Center of the National Institutes of Health. Patients aged 18 years and older are eligible to participate.

Clear cell sarcoma of soft tissue

Clear cell sarcoma (formerly and inappropriately called malignant melanoma of soft parts), also called clear cell sarcoma of tendons and aponeuroses, is somewhat similar to cutaneous malignant melanoma but is cytogenetically distinct; most cases have a t(12;22)(q13;q12) translocation that has not been reported in melanoma.[91] In one series, clear cell sarcoma demonstrated a propensity to metastasize to regional lymph nodes (12%–43%).[92]

The primary treatment for clear cell sarcoma is complete surgical resection, with the addition of radiation therapy for uncertain or involved margins. Chemotherapy is rarely effective.[94]; [95][Level of evidence: 3iiDii]

Desmoplastic small round cell tumor

Desmoplastic small round cell tumor is a primitive sarcoma that most frequently involves the abdomen, pelvis, or tissues around the testes.[96,97,98] The tumor occurs more commonly in males and may spread to the lungs and elsewhere. Peritoneal and pelvic lesions frequently have widespread peritoneal implants.[99] In a large, single-institution series of 65 patients, a correlation was made between computed tomography (CT) scans in most patients and positron-emission tomography (PET)/CT scans in 11 patients. PET/CT scans had very few false-negative results and detected metastatic sites missed on conventional CT scans.[99]

Cytogenetic studies of these tumors have demonstrated the recurrent translocation t(11;22)(p13;q12), which has been characterized as a fusion of the WT1 and EWS genes.[100]

Treatment

There is no standard approach to the treatment of desmoplastic small round cell tumor. Complete surgical resections are rare, and the overall prognosis for desmoplastic small round cell tumor remains extremely poor, with reported rates of death at 90%. A small series of patients who were treated with hyperthermic intraperitoneal chemotherapy with acceptable toxicity has been reported.[101]

Greater than 90% tumor resection either at presentation or after neoadjuvant chemotherapy may be a favorable prognostic factor for OS.[102,103] Treatment may include chemotherapy, surgery, and radiation therapy. Multiagent chemotherapy analogous to that used for sarcomas has been used, as well as total abdominal radiation therapy.[96,97,102,104,105]

Epithelioid sarcoma

Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis which displays multilineage differentiation.[106] It is characterized by inactivation of the SMARC gene, which is present in both conventional and proximal types of epithelioid sarcoma.[107]

Epithelioid sarcoma commonly presents as a slowly growing firm nodule based in the deep soft tissue; the proximal type predominantly affects adults and involves the axial skeleton and proximal sites. The tumor is highly aggressive and has a propensity for lymph node metastases.

In a review of 30 pediatric patients with epithelioid sarcoma (median age at presentation, 12 years), responses to chemotherapy were reported in 40% of patients using sarcoma-based regimens, and 60% of patients were alive at 5 years after initial diagnosis.[108] A single-institution retrospective review of 20 patients, including children and adults, found no difference in the probability of recurrence between patients who received chemotherapy and those who did not receive chemotherapy and suggested that radiation therapy may be useful. Surgical removal of primary and recurrent tumor(s) was most effective.[109][Level of evidence: 3iiiA]

Benign PEComas are common in tuberous sclerosis, an autosomal dominant syndrome that also predisposes to renal cell cancer and brain tumors. Tuberous sclerosis is caused by germline inactivation of either TSC1 (9q34) or TSC2 (16p13.3), and the same tumor suppressor genes are inactivated somatically in sporadic PEComas.[110] Inactivation of either gene results in stimulation of the mTOR pathway, providing the basis for the treatment of nonsurgically curable PEComas with mTOR inhibitors.[111,112]

PEComas occur in various rare gastrointestinal, pulmonary, gynecologic, and genitourinary sites. Soft tissue, visceral, and gynecologic PEComas are more commonly seen in middle-aged female patients and are usually not associated with the tuberous sclerosis complex.[113] Most PEComas have a benign clinical course, but malignant behavior has been reported and can be predicted based on the size of the tumor, mitotic rate, and presence of necrosis.[114]

Extrarenal (extracranial) rhabdoid tumor

Malignant rhabdoid tumors were first described in children with renal tumors in 1981 (refer to the Wilms Tumor and Other Childhood Kidney Tumors Treatment summary for more information) and were later found in a variety of extrarenal sites. They are uncommon and highly malignant, especially in children younger than 2 years. The first sizeable series of 26 childhood patients with extrarenal extracranial malignant rhabdoid tumor of soft tissues came from patients enrolled on the Intergroup Rhabdomyosarcoma Studies I through III during a review of pathology material. Only five patients (19%) were alive without disease.[115] Later, investigation of children with atypical teratoid/rhabdoid tumors of the brain, as well as those with renal and extrarenal malignant rhabdoid tumors, found germline and acquired mutations of the SMARCB1 gene in all 29 tumors tested.[116] Rhabdoid tumors may be associated with germline mutations of the SMARCB1 gene and may be inherited from an apparently unaffected parent.[117] This observation was extended to 32 malignant rhabdoid tumors at all sites in patients whose mean age at diagnosis was 12 months.[118] The disease can occur congenitally [119] and is uncommon in older children and adults.

In a Surveillance, Epidemiology, and End Results (SEER) study of 229 patients with renal, central nervous system, and extrarenal malignant rhabdoid tumor, patients aged 2 to 18 years, limited extent of tumor, and delivery of radiation therapy were shown to affect the outcome favorably compared with other patients (P < .002 for each comparison). Site of the primary tumor was not prognostically significant. OS at 5 years was 33%.[120]

Treatment includes surgical removal when possible, chemotherapy as used for STSs (but no single regimen is currently accepted as best), and radiation therapy.[121][Level of evidence: 3iA]; [122,123][Level of evidence: 3iiiB]

Extraskeletal myxoid chondrosarcoma

Extraskeletal myxoid chondrosarcoma is relatively rare among STSs, representing only 2.3% of all STSs.[124] It has been reported in children and adolescents.[125]

Extraskeletal myxoid chondrosarcoma is a multinodular neoplasm. The rounded cells are arranged in cords and strands in a chondroitin sulfate myxoid background. Several cytogenetic abnormalities have been identified (see Table 2), with the most frequent being the translocation t(9;22)(q22;q12), involving the EWSR1/NR4A3 genes.[126] The tumor has traditionally been considered of low-grade malignant potential.[127] However, recent reports from large institutions showed that extraskeletal myxoid chondrosarcoma has significant malignant potential, especially if patients are followed for a long time.[128,129] Patients tend to have slow protracted courses. Nodal involvement has been well described. Local recurrence (57%) and metastatic spread to lungs (26%) have been reported.[129]

Treatment

The therapeutic benefit of chemotherapy has not been established. Aggressive local control and aggressive resection of metastases led to OS of 87% at 5 years and 63% at 10 years.[128] There may be potential genetic targets for small molecules, but these should be studied as part of a clinical trial.

Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor

(Refer to the PDQ summary on Ewing Sarcoma Treatment for more information.)

Synovial sarcoma

Synovial sarcoma is one of the most common nonrhabdomyosarcomatous STSs in children and adolescents. In a SEER review from 1973 to 2005, 1,268 patients with synovial sarcoma were identified. Approximately 17% of these patients were children and adolescents and the median age at diagnosis was 34 years.[130] The most common location is the extremities, followed by trunk and head and neck.[130] Patients younger than 10 years have more favorable outcomes and clinical features, including extremity primaries, smaller tumors, and localized disease, than do older patients.[130]

Synovial sarcoma can be subclassified as the following types:

Monophasic fibrous type.

Biphasic type with distinct epithelial and spindle cell components.

Poorly differentiated. Poorly differentiated synovial sarcoma has features of monophasic or biphasic synovial sarcoma but also has a variable proportion of poorly differentiated areas characterized by high cellularity, pleomorphism, and polygonal or small round-cell morphology, numerous mitoses, and often necrosis.[131]

The diagnosis of synovial sarcoma is made by immunohistochemical analysis, ultrastructural findings, and demonstration of the specific chromosomal translocation t(x;18)(p11.2;q11.2). This abnormality is specific for synovial sarcoma and is found in all morphologic subtypes. Synovial sarcoma results in rearrangement of the SYT gene on chromosome 18 with one of the subtypes (1, 2, or 4) of the SSX gene on chromosome X.[132,133] It is thought that the SYT/SSX18 transcript promotes epigenetic silencing of key tumor suppressor genes.[134] Reduced INI1 nuclear reactivity on immunohistochemical staining is typical of most synovial sarcomas examined and does not occur with other similar histologies, thus providing a fast diagnosis while awaiting genetic studies.[135]

The most common site of metastasis is the lung.[136,137] The risk of metastases is highly influenced by tumor size; it is estimated that patients with tumors that measure greater than 5 cm have a 32-fold risk of developing metastases when compared with other patients.

In a retrospective analysis of synovial sarcoma in children and adolescents who were treated in Germany and Italy, tumor size (>5 cm or ≤5 cm in greatest dimension) was an important predictor of EFS.[138] In this analysis, local invasiveness conferred an inferior probability of EFS, but surgical margins were not associated with clinical outcome. In a single-institution retrospective analysis of 111 patients with synovial sarcoma who were younger than 22 years at diagnosis, larger tumor size, greater depth in tissue, greater local invasiveness, and more proximal tumor location were associated with poorer OS.[139][Level of evidence: 3iiA] A multicenter analysis of 219 children from various treating centers including Germany, SJCRH, Instituto Tumori, and MD Anderson Cancer Center reported an estimated 5-year OS of 80% and EFS rate of 72%. In this analysis, an interaction between tumor size and invasiveness was observed; in multivariate analysis, patients with large or invasive tumors or with Intergroup Rhabdomyosarcoma Study Clinical Group III and IV disease had decreased OS. Treatment with radiation therapy was related to improved OS (hazard ratio, 0.4; 95% confidence interval, 0.2–0.7). In Intergroup Rhabdomyosarcoma Study Group III patients, objective response to chemotherapy (18 of 30 [60%]) correlated with improved survival. In adults, factors such as International Union Against Cancer/American Joint Committee on Cancer stage III and stage IVA, tumor necrosis, truncal location, elevated mitotic rate, age, and histologic grade have been associated with a worse prognosis.[140,141,142] Expression and genomic index prognostic signatures have been studied in synovial sarcoma. More complex genomic profiles, with greater rearrangement of the genome, are more common in adults than in younger patients with synovial sarcoma and are associated with a higher risk for metastasis.[143]

Treatment

Synovial sarcoma appears to be more sensitive to chemotherapy than many other STSs, and children with synovial sarcoma seem to have a better prognosis when compared with adults.[5,137,142,144,145,146,147,148,149] The most commonly used regimens for the treatment of synovial sarcoma incorporate ifosfamide and doxorubicin.[147,150,151] Response rates to the ifosfamide and doxorubicin regimen are higher than in other nonrhabdomyosarcomatous STSs.[152] A meta-analysis also suggested that response to chemotherapy was correlated with improved survival.[151]

Several treatment centers advocate adjuvant chemotherapy after resection and radiation therapy of synovial sarcoma in children and young adults.[138,148,151,153,154,155] The International Society of Pediatric Oncology-Malignant Mesenchymal Tumors studies showed that select patients (young age, < 5 cm resected tumors) with nonmetastatic synovial sarcoma can have excellent outcome in the absence of radiation, but it is still unclear whether that approach obviates an advantage of radiation for local or regional control.[154] A German trial suggested a benefit for adjuvant chemotherapy in children with synovial sarcoma.[155] A meta-analysis also suggested that chemotherapy may provide benefit.[151] However, unequivocal proof of the value of adjuvant chemotherapy from prospective, randomized clinical trials is lacking and the results of COG-ARST0332 are pending. Survival after relapse is poor (30% at 5 years). Factors associated with outcome after relapse include duration of first remission (> or ≤ 18 months) and lack of a second remission.[156]

Undifferentiated sarcoma; sarcoma, NOS

Patients with undifferentiated STS had been eligible for participation in rhabdomyosarcoma trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group (COG) from 1972 to 2006. The rationale was the observation that patients with undifferentiated STS had similar sites of disease and outcome as those with alveolar rhabdomyosarcoma. Therapeutic trials for adults with STS include patients with undifferentiated STS and other histologies, which are treated similarly, using ifosfamide and doxorubicin, and sometimes with other chemotherapy agents, surgery, and radiation therapy. Currently in the COG, they are treated on clinical trials for patients with nonrhabdomyosarcomatous STSs.

Vascular Tumors

Vascular tumors vary from hemangiomas, which are always considered benign, to angiosarcomas, which are highly malignant.[157] Vascular tumors include the following tumor subtypes:

Epithelioid hemangioendothelioma.

Angiosarcoma (deep).

Hemangiopericytoma (infantile).

Epithelioid hemangioendothelioma

Hemangioendotheliomas are tumors found in infants that arise within the liver or elsewhere and usually remain benign.[158,159] Liver hemangioendotheliomas may regress then enlarge. These tumors may also become malignant. The tumors are sometimes associated with consumptive coagulopathy, also known as the Kasabach-Merritt syndrome (or phenomenon).[160,161,162,163] Chemotherapy and interferon have had some benefit in isolated cases of hemangioendothelioma associated with Kasabach-Merritt syndrome.[161,162] A report from Spain indicated good control of severe thrombocytopenia of less than 30,000/mm3 in 11 patients with hemangioendothelioma or tufted angioma treated with weekly vincristine, and daily low-dose aspirin and ticlodipine.[164][Level of evidence: 3iiiA]

In older children and adults, hemangioendotheliomas may occur elsewhere in the body and can metastasize to lungs, lymph nodes, bones, and within the pleural or peritoneal cavities. The preferred pathologic designation for these lesions in older persons is epithelioid hemangioendothelioma, which connotes the possibility of distant spread. These latter lesions are considered to be of intermediate malignant potential, between benign hemangioma and angiosarcoma.[165,166] Epithelioid hemangioendothelioma of the liver is usually managed surgically. Some patients may need orthotopic liver transplantation because this disease does not respond to radiation therapy or chemotherapy.[165] In more extensive hemangioendothelioma, inhibition of the mTOR pathway may be helpful.[167] However, this should be investigated as part of a clinical trial before use in the clinical setting.

Treatment of asymptomatic liver hemangioendothelioma in a child younger than 1 year may include close observation, because some tumors will regress. Symptomatic lesions require urgent medical or surgical management, especially if coagulopathy is present.[158,160,161,162,164]

Angiosarcoma (deep)

Angiosarcomas may arise in a setting of benign vascular anomalies or vascular malformations.[168,169,170] Angiosarcomas have also been described in previously benign hemangiomas and hemangioendotheliomas.[159] Of five girls, three infants younger than 4 months with cutaneous hemangiomas and two girls with multinodular liver hemangiomas developed angiosarcomas.[159] All three girls initially diagnosed with cutaneous hemangiomas died. Liver size initially decreased; however, at age 2.5 to 5 years, their livers enlarged, and all three girls died of angiosarcoma. The other two girls presented with vascular liver tumors at age 2 and 3.5 years, without previous histories. The younger girl had a benign unifocal hemangioendothelioma on biopsy; 3 months later, another biopsy showed both benign and malignant histology, and she died. The older girl had multinodular angiosarcomas without metastases, underwent liver transplantation, and was recurrence free 2 years later. The authors recommend liver ultrasound surveillance every 6 months for infants with multinodular liver hemangiomas.

Complete surgical excision appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence of tumor shrinkage in some patients in response to local or systemic therapy.[171,172,173,174] A review of 222 patients (median age, 62 years; range, age 15–90 years) showed an overall disease-specific survival (DSS) rate of 38% at 5 years. Five-year DSS was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis.[174] Data on liver transplantation for localized angiosarcoma are limited.[175][Level of evidence: 3iiA]

Chemotherapy may be effective for the treatment of angiosarcoma. A review of 20 years of experience in the Italian and German Soft Tissue Sarcoma Cooperative Group identified 12 children with angiosarcoma.[173] One objective response to chemotherapy was observed, and the overall behavior of this tumor was identical to angiosarcoma in adults. A subsequent retrospective study of 14 children with angiosarcoma performed by the Polish and German Cooperative Paediatric Soft Tissue Sarcoma Study Groups identified four chemotherapy responses in ten children.[176] Another review of 15 patients demonstrated a 33% survival rate.[168]

Anti-angiogenesis therapy may prove useful in the treatment of this group of neoplasms.[177]

Hemangiopericytoma (infantile)

Hemangiopericytoma is a highly vascularized tumor of uncertain origin. Hemangiopericytoma in children younger than 1 year seems to have a better prognosis than in children older than 1 year.[178,179,180] Histologically, hemangiopericytomas are composed of packed round or fusiform cells that are arranged around a complex vasculature, forming many branch-like structures. Hyalinization is often present. Infantile hemangiopericytomas have similar histology but many are multilobular with vasculature outside the tumor mass.[181]

In a series of 17 children, the differences in metastatic potential and response to treatment were clearly demonstrated for adult and infantile hemangiopericytomas.[37] Eleven children were older than 1 year. Several of these patients had disease in the lymph nodes or lungs. Six patients with stage II and III disease progressed and died. Three patients with stage I disease survived, although one had recurrence in the lungs. Six patients had infantile hemangiopericytoma, most were greater than stage I (5 of 6). All six survived and three had good responses to vincristine, actinomycin, and cyclophosphamide.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with nonmetastatic childhood soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

The prognosis for children with metastatic STSs is poor,[1,2,3,4,5,6] and these children should receive combined treatment with chemotherapy, radiation therapy, and surgical resection of pulmonary metastases. In a prospective randomized trial, chemotherapy with vincristine, dactinomycin, doxorubicin, and cyclophosphamide, with or without dacarbazine, led to tumor responses in one-third of patients with unresectable or metastatic disease. The estimated 4-year survival rate, however, was poor, with fewer than one-third of children surviving.[6,7,8]

Pulmonary Metastases

Children with isolated pulmonary metastases should undergo a surgical procedure in an attempt to resect all gross disease. For patients with multiple or recurrent pulmonary metastases, additional surgical procedures can be performed if the morbidity is deemed acceptable. In a retrospective review, patients with synovial sarcoma and pulmonary metastases for whom it was possible to completely resect all metatatic lung lesions had better survival than did patients for whom it was not possible to achieve complete resections.[9][Level of evidence: 3iiiA] An alternative approach is focused radiation therapy (fractionated stereotactic radiation therapy), which has been successfully used in adults to sterilize lesions. The estimated 5-year survival rate after thoracotomy for pulmonary metastasectomy has ranged from 10% to 58% in adult studies. Emerging data suggest a similar outcome after the administration of focused radiation therapy in adults.[10] Formal segmentectomy, lobectomy, and mediastinal lymph node dissection are unnecessary.[11]

Treatment Options Under Clinical Evaluation

The following agents are being studied for the treatment of certain metastatic STSs:

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with metastatic childhood soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Treatment of Progressive / Recurrent Childhood Soft Tissue Sarcoma

With the possible exception of infants with infantile fibrosarcoma, the prognosis for patients with recurrent or progressive disease is poor. No prospective trial has been able to prove that enhanced local control of pediatric soft tissue sarcomas (STSs) will ultimately improve survival. Therefore, treatment should be individualized for the site of recurrence and biologic characteristics (e.g., grade, invasiveness, and size) of the tumor.

Decisions about treatment options for progressive or recurrent childhood STS are based on many factors, including the following:

Site of recurrence.

Tumor biologic characteristics.

Prior therapies.

Individual patient considerations.

Treatment options for recurrent or progressive disease include the following:

Surgical excision of local recurrence or isolated pulmonary recurrence.

Surgical excision of local recurrence followed by radiation therapy or brachytherapy (if no prior radiation therapy was given).

Limb amputation (only for some children with extremity sarcomas that have already received radiation therapy).

A phase I trial of pazopanib reported one partial response in a patient with desmoplastic small round cell tumor and prolonged disease stabilization in eight patients with recurrent sarcoma.[5][Level of evidence: 2Diii]

A clinical trial of new chemotherapeutic regimens.

Resection is the standard treatment for recurrent pediatric nonrhabdomyosarcomatous STSs. If the patient has not yet received radiation therapy, adjuvant radiation should be considered after local excision of the recurrent tumor. Limb-sparing procedures with adjuvant brachytherapy have been evaluated in adults but have not been studied extensively in children. For some children with extremity sarcomas who have received previous radiation therapy, amputation may be the only therapeutic option.

Pulmonary metastasectomy may achieve prolonged disease control for some patients.[6] A large, retrospective analysis of patients with recurrent STS showed that isolated local relapse had a better prognosis and that resection of pulmonary metastases improved the probability of survival.[7] In 31 children and adolescents younger than 23 years with pulmonary metastases from synovial sarcoma, complete resection of lung metastases appeared to prolong survival when compared with ten other patients who were not considered candidates for metastasectomy.[8][Level of evidence: 3iiiA] All patients with recurrent tumors should be considered for current clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Added text to state that a report from Spain indicated good control of severe thrombocytopenia of less than 30,000/mm3 in 11 patients with hemangioendothelioma or tufted angioma treated with weekly vincristine, and daily low-dose aspirin and ticlodipine (added level of evidence 3iiiA).

Treatment of Metastatic Childhood Soft Tissue Sarcoma

Added text to state that in a retrospective review, patients with synovial sarcoma and pulmonary metastases for whom it was possible to completely resect all metastatic lung lesions had better survival than did patients for whom it was not possible to achieve complete resections (cited Stanelle et al. as reference 9 and level of evidence 3iiiA).

Treatment of Progressive/Recurrent Childhood Soft Tissue Sarcoma

Added text to state that a phase I trial of pazopanib reported one partial response in a patient with desmoplastic small round cell tumor and prolonged disease stabilization in eight patients with recurrent sarcoma (cited Glade et al. as reference 5 and level of evidence 2Diii).

Added text to state that in 31 children and adolescents younger than 23 years with pulmonary metastases from synovial sarcoma, complete resection of lung metastases appeared to prolong survival when compared with ten other patients who were not considered candidates for metastasectomy (cited Stanelle et al. as reference 8 and level of evidence 3iiiA).

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood soft tissue sarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,

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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.

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